Substituted l



United States Patent 3 12s 27s sussriruran Lil-DEEFLZNYLd-(l-PWERHDYD-BUTANOL-i nsmvarrvns Paul N. (Zraig, Roslyn, and Charles L. Zhhle,Berwyn,

& French Laboratories,

of Pennsylvania This invention relates to novel substituted piperidinobutanols having valuable pharmacological activity. More specificallythis invention relates to substituted1,1-diphenyl-4-(l-piperidyD-butanol-l derivatives having antiemeticactivity, free from limiting side effects.

The compounds of this invention are particularly useful as antierneticsboth by virtue of their chemical structure and pharmacological profile.Being non-phenothiazines, the compounds are devoid of the side effectsencountered with the phenothiazine class of antiemetics. The compoundsof this invention and in particular the trifluoromethyl substitutedderivative, have a low toxicity and further at eifective antiemeticdosages they lack the atropine-like side efiects such as mydriasis anddryness of the mouth which are sometimes encountered with unsubstitutedpiperidyl butanols. Although these side effects are not limiting in theunsubstituted series, the surprising lack of these effects in thesubstituted compounds of this invention results in a very favorabletherapeutic ratio. In addition the substituted compounds of thisinvention have a longer duration of antiemetic activity in comparison tounsubstituted piperidyl butanols.

More specifically the compounds of this invention are represented by thefollowing structural formula:

FORMULA I O-CH GHgOHg-N when R represents trifluoromethyl or chlorine,preferably trifiuoromethyl.

It is a surprising [result of this invention that of the possible R monosubstituted ortho, meta and para position isomers, only the parasubstituted compounds of Formula I have useful antiemetic activity, theortho and metal substituted compounds being considerably less active.

The nontoxic pharmaceutically acceptable acid addi tion salts of thecompounds of the above formula are also included Within the scope ofthis invention. Such salts are easily prepared by methods known to theart. The base is reacted with either the calculated amount of organic orinorganic acid in aqueous miscible solvent, such as acetone or ethanol,with isolation of the salt by concentration and cooling or an excess ofthe acid in aqueous immiscible solvent, such as ethyl ether orchloroform, with the desired salt separating directly. Exemplary of suchorganic salts are those with maleic, fiumaric, benzoic, ascorbic,pamoic, succinic, bismethylenesalicylic, methanesulfonic,ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric,gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic,stearic, palmitic, itaconic, glycolic, p amlinobenzoic, glutamic,benzene sulfonic and theophylline acetic acids as well as with the8-halotheophyllines, for example, S-bromotheophylline. Exemplary of suchinorganic salts are those with hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric and nitric acids. Of course these salts may also beprepared by the classical method of double decomposition of appropriatesalts which is Well-known to the art.

The compounds of this invention are generally prepared 3,128,278Patented Apr. 7, 1964 "ice by reacting the appropriately substitutedbenzophenone with the Grignard reagent of 1-(3-chloropropyl)-piperidine.The reaction is advantageously carried out in tetrahydrofuran solution,although other similar non-reactive organic ether-type solvents may beemployed, at reflux temperature for from 1 to 4 hours. Hydrolysis of theintermediate Grignard complex is accomplished with ice water and forexample ammonium chloride. Cooling and/or removal of all solvents yieldsthe free base which is distilled or recrystallized and optionallyconverted to an acid addition salt as described above.

Of course the compounds of this invention may be present as d and loptical isomers as well as the racemic mixture by virtue of theasymmetry at carbon-l. The racemic mixture may be conveniently separatedinto the optical isomers by standard resolution procedures with forexample d-tartaric acid. In this specification and claims it is intendedby the structural formulas to include both the r-acemic mixtures and theseparated d and l isomers.

The compounds of this invention are combined with a pharmaceuticalcarrier for internal administration to animals, including human beings,in an amount suflicient to produce antiemetic effects. Such carriers areeither solid or liquid. Exemplary of solid pharmaceutical earriers arelactose, corn-starch, mannitol, talc, etc. The compounds of thisinvention are mixed with the carrier and filled into hard gelatincapsules or tableted with suitable tableting aids such as magnesiumstearate, starch or other lubricants, desintegrants or coloring agents.It combination with a liquid carrier is desirable, a soft gelatincapsule is filled with a slurry of the novel com pounds in soybean orpeanut oil. Aqueuos suspensions or solutions are prepared for alternateoral or parenteral administration.

The dosage unit comprising a compound of this invention and apharmaceutical carrier contains from about 10 mg. to about mg. ofmedicament, advantageously from about 20 mg. to about 30 mg. per dosageunit. The medicament in such dosage units is administered orally orparenterally until a satisfactory antiemetic response is obtained. Thedaily dosage is from about 10 mg. to about 30 0 mg. of medicament,advantageously from about 20 mg. to about 2.00 mg. When the methoddescribed above is carried out, nausea and vomiting are controlledrapidly and effectively.

The following examples set forth the preparation of the compounds ofFormula I.

Example 1 A solution of 15.0 g. of l-(3-chloropropyl)-piperidine(obtained from the alkylation of piperidine with l-bromo-3-chl0ropropane) in 50 ml. of tetrahydrofuran is added to 2.4 g. ofmagnesium in 50 ml. of tetrahydrofuran with some initial heating. Whenthe addition is complete, 15.0 g. of 4-tnifluoromethylbcnzophenone in 50ml. 01f tetrahydrofuran is added and the mixture is refluxed and stirredfor 23 hours. Hydrolysis of the reaction mixture in the cold and removalof solvents yielded l-phenyl-1-(4-trifluoromethylphenyl)-4-(l-piperidyD-butanol-l as an oil which isdistilled, B.P. 154-l56 C. at 0.2 mm.

A portion of the free base converted to the maleate salt in ethylacetate solution. Melting point of the maleate is 128-129 C.

Example 2 A solution of 15.0 g. of l-(3-chloro-propyl)piperidine in 50ml. of tetrahydrofuran is added to a mixture of 2.4 g. of magnesium in50' of tetrahydrofuran. When the addition is complete, 13.0 g. of4-chlorobenzophenone in 50 ml. of tetrahydrofuran is added and themixture is refluxed for 2-3 hours. Hydrolysis and workup yields 3 e1-(4-chlorophenyl)1-phenyl-4-( 1-piperidyl) butanol-1. A 3. A compoundof the formula: portion of the free base is converted to the maleatesalt, M.P. 128-129 c. \o11 What 118 claimed is! I CIJ CH2CHQOHZ N 1. Acompound selected from the group consisting of 5 i a free base havingthe following formula: 01

4. l-phenyl-1-(4-trifiuoromethylphenyl) 4 (l-p iperi- \(|)HdyD-butanol-I maleate.

10 References Cited in the file of this patent Q UNITED STATES PATENTS2,649,444 Barrett Aug. 18, 1953 m whlch R 1s :a member selected from thegroup consisting of tn'fiuoromethyl and chloro, and the nontoxic 15FOREIGN PATENTS pharmaceutically acceptable acid addition salts thereof.682,160 Great Britain Nov. 5, 1952 2. A compound of the formula: 682,161Great Britain Nov. 5, 1952 OTHER REFERENCES Ose et al.: ChemicalAbstracts, vol. 54, page 17,335

OHzOHzCHzN (1960). EQ/ Yale: J. Med. and Pharm. Chem," vol. 1, No. 2,page

4. 1-PHENYL-1-(4-TRIFLUOROMETHYLPHENYL) -4 - (1-PIPERIDYL)-BUTANOL-1MALEATE.